Development of New Method for Construction of Chiral, Non-Racemic Quaternary Carbon Center by Enzymatic Acylation of Alcohols and Application Thereof

醇酶酰化构建手性非外消旋季碳中心新方法的开发及其应用

• 批准号: 13672214
• 负责人: AKAI Shuji
• 金额: $ 2.3万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672214/
• 关键词: lipase; ethoxyvinyl ester; chiral, non-racemic quaternary carbon center; cycloaddition; asymmetric desymmetrization; oxindole; domino reaction; nitrone; 双極子付加環化反応; ジオール; タンデム不斉合成; 分子内 Diels-Alder反応

Construction of chiral, non-racemic quaternary carbon center via enzymatic acylation of alcohols is believed to be an effective environmentally benign process because of its high enantioselectiviry and safe and easy operation; however, the successful examples have been limited. This is mainly due to the problems of the currently-best method using vinyl esters, which involve inactivation of the enzymes and easy racemication via intramolecular acyl group migration. Recently, we have disclosed their resolution by using 1-ethoxyvinyl esters (EVEs), leading to the discovery of the first effective enzymatic desymmetrization of symmetric diols and the first domino asymmetric reactions. This project has aimed at the expansion of these methods for the construction of chiral, non-racemic quaternary carbon centers and also their application for asymmetric synthesis of leading compounds for new drug discovery. The followings are summary of the results:1. The enzymatic desymmetrization method was e … More ffective for wide range of 1,2- and 1,3-diols, and a new general method for the construcntion of chiral, non-racemic quaternary carbon centers has been established. This protocol was successfully applied for asymmetric synthesis of either enantiomer of the ABCDE-analog of antitumor antibiotic fredericamycin A and also for asymmetric preparation of the various oxindoles (86- 98% ee) with a chiral, non-racemic quaternary carbon center at the C-3 position and a variety of N-1 protective group.2. The lipase-catalyzed domino asymmetric synthesis was applied to various furfuryl alcohol to provide a one-pot synthesis of 7-oxabicycloheptenes (91- 99% ee) with a chiral quaternary carbon center. Especially, useful chiral synthons bearing a vinyl bromide moiety were prepared from the 3-bromofurfuryl alcohols. The first domino process involving dynamic kinetic resolution was achieved by the similar reaction of α-hydroxynitrones to give aza-polycyclic products in good yields. The asymmetric total synthesis of a natural pyrrolizidine alkaloid, rosmarinecine, was attained in 3 steps from a readily available racemic hydroxynitrone and a maleic acid. Less

通过酶催化酰化醇类化合物构建手性非外消旋季碳中心是一种环境友好的方法，具有高的对映选择性和安全性，但成功的实例并不多。这主要是由于目前使用乙烯基酯的最佳方法的问题，其涉及酶的失活和通过分子内酰基迁移容易外消旋化。最近，我们已经公开了他们的决议，通过使用1-乙氧基乙烯基酯（EVE），导致发现的第一个有效的酶解对称的对称二醇和第一个多米诺不对称反应。该项目旨在扩展这些方法用于构建手性，非外消旋季碳中心，以及它们在新药发现的领先化合物的不对称合成中的应用。主要研究结果如下：1.采用酶法去对称化方法， ...更多信息 对1，2-和1，3-二醇都是有效的，并建立了一种新的手性非外消旋季碳中心的通用构建方法。该方法成功地应用于抗肿瘤抗生素fredericamycin A的ABCDE类似物的对映体的不对称合成，以及在C-3位具有手性非外消旋季碳中心和各种N-1保护基的各种羟吲哚（86- 98%ee）的不对称制备.将脂肪酶催化的多米诺不对称合成应用于不同的糠醇，以提供具有手性季碳中心的7-氧杂双环庚烯（91- 99%ee）的一锅合成。特别地，从3-溴糠醇制备了有用的带有溴乙烯基部分的手性配体。第一个涉及动态动力学拆分的多米诺过程是通过α-羟基硝酮的类似反应实现的，以良好的产率得到氮杂多环产物。以易得的外消旋羟基硝酮和马来酸为原料，经3步不对称全合成了天然吡咯里西啶生物碱迷迭香碱。少

项目成果

AKAI, Shuji: "Lipase-Gatalyzed Domino Kinetic Resolution/Intramolecular Diels-Alder Reaction: One-Pot Synthesis of Optically Active 7-Oxabicyclo[2.2.1]heptenes from Furfuryl Alcohols and β-Substituted Acrylic Acids"Chemistry-A European Journal. 8. 4255-42

AKAI，Shuji：“脂肪酶催化多米诺动力学拆分/分子内狄尔斯-阿尔德反应：从糠醇和 β-取代丙烯酸中一锅合成光学活性 7-氧杂双环[2.2.1]庚烯”Chemistry-A 欧洲杂志。 8.4255-42

AKAI, Shuji: "Development of Lipase-Catalyzed Novel Asymmetric Synthesis"The Production & Technique. 53. 57-60 (2001)

赤井修二：“脂肪酶催化新型不对称合成的开发”的生产

AKAI, Shuji: "Lipase-Catalyzed Enantioselective Desymmetrization of Prochiral 3,3-Bis(hydroxymethl)oxindoles"Tetrahedron Letters. 42. 7315-7317 (2001)

AKAI，Shuji：“脂肪酶催化的前手性 3,3-双（羟甲基）羟吲哚的对映选择性去对称化”四面体字母。

赤井 周司: "リパーゼの不斉識別能を活用する新規不斉合成反応の開発研究"生産技術誌. 53. 57-60 (2001)

赤井修二：“利用脂肪酶手性辨别能力的新型不对称合成反应的开发研究”《生产技术杂志》53. 57-60 (2001)。

Akai, Shuji: "An Efficient Lipase-Catalyzed Enantioselective Desymmetrization of Prochiral 2,2-Disubstituted 1,3-Propanediols and Meso 1,2-Diols Using 1-Ethoxyvinyl 2-Furoate"Journal of Organic Chemistry. 67. 411-419 (2002)

Akai, Shuji：“使用 1-乙氧基乙烯基 2-糠酸酯对前手性 2,2-二取代 1,3-丙二醇和内消旋 1,2-二醇进行有效的脂肪酶催化对映选择性去对称化”有机化学杂志。